Abstract Twenty to thirty percent of people who develop epilepsy continue to have seizures despite antiepileptic drug (AED) treatment. The introduction of many new AEDs in the last two decades does not appear to have reduced substantially the proportion of people who are pharmacoresistant and continue to have seizures. Currently there are two main mechanisms suggested for pharmacoresistance in people with epilepsy: the transporter and target hypothesis. There are inadequacies in both these hypotheses and alternatives should be considered. There is accumulating evidence from animal studies, human physiological measurements and imaging studies that there is impaired mitochondrial energy production in the epileptogenic zone. Impaired mitochondrial function and lower bioenergetic state is associated with higher extracellular glutamate and increased neuronal hyperexcitability. Conversely, the ketogenic diet effective in reducing seizures, has been shown in animal studies to be associated with up-regulation of mitochondrial genes and increased mitochondrial biogenesis. A human imaging study has also shown improved cerebral energy metabolism in people on a ketogenic diet. Hence, the hypothesis is that the likelihood of seizures occurring results mainly from the interplay of three factors: the seizuregenic potential of the epileptic focus, the efficacy of AEDs and the efficiency of mitochondrial function. This hypothesis can be tested by comparing mitochondrial function in people with epilepsy who are pharmacoresistant with those who have become seizure free. The implication of the hypothesis is that the management of epilepsy should take account of the many drugs, toxins, nutrition and lifestyle factors that are known to affect mitochondrial function.